The therapeutic care of the patients having cancer is primarily based on surgery, radiotherapy and chemotherapy which have to be used according to standard protocols. The curative surgery consists in removal of all the tumoral mass. However, this is not always possible to guarantee the absence of any residual disease after the ablation of the observable part of the tumour, even by experienced surgeons. This is why the surgery is generally used in combination is with radiotherapy and/or chemotherapy. Chemotherapy and/or radiotherapy can be used as neoadjuvant therapy or auxiliary or adjuvant therapy, or alone when the surgery is impossible. Neoadjuvant therapy is usually used when the tumoral mass is too important and requires a reduction before surgery. Auxiliary or adjuvant chemotherapy is used to treat the residual tumoral diseases and to limit the local recurrences or the metastatic relapses. When a tumour is detected at an inoperable stage, then the therapeutic care is only based on chemotherapy and/or radiotherapy. Surgery is marginally used in this context and has palliative objectives.
In any case, the choice of chemotherapy always raises the following questions: Which drug or combination of drugs is adapted to this type of cancer? What is the most adapted therapeutic strategy for this patient? What are the chances for observing a therapeutic benefit with the selected drugs?
The current medical practice consists in treating the patients according to the existing therapeutic protocols. In the majority of the cases, the choice of the therapeutic protocol is based on the anatomo-pathological and clinical data. These protocols apply in first, second, even third therapeutic line. When there is therapeutic failure, or for the metastatic stages, certain patient are included in clinical trials generally using broad selection criteria defining primarily, the location of the primitive tumour, the extension of the disease, the situation of the vital functions of the patient and certain specific contraindications of the drug under trial. Whatever the therapeutic approach (standard or clinical trial), only part of the treated population profits from the treatment whereas the remainder of the patients do not respond and show a progressing disease even under treatment.
To improve this situation, since many years, physicians and researchers are trying to identify markers for predicting the efficacy of the treatments for a given patient and to be able to adapt the treatment of each patient. Thus the concept of personalized medicine consists in adapting the therapeutic decision according to the anatomo-pathological, clinical characteristics but especially of the biological characteristics of the tumour.
Several examples are known without representing a solution useful for any patient having a cancer.
A first approach was the so-called “test-companion” assay, used for the first time for the trastuzumab (Herceptin®), a monoclonal antibody targeting the Her2/Neu receptor. In breast cancers, this drug is administered only when an amplification/overexpression of this receptor is observed. However, this overexpression does not guarantee a therapeutic response. Some resistances to Herceptin® can be explained by an activation of the Akt pathway, for instance. The association of an mTOR inhibitor (targeting the Akt pathway) can restore the sensitivity to Herceptin. Nevertheless, for some patients, the therapeutic benefit was observed in the absence of an amplification of the receptor.
The measurement of the expression level of the Her2 receptor is the first example of test companion and the majority of pharmaceutical companies or researchers are trying to reproduce this model considered as the first example of personalized medicine. The following examples are relevant to illustrate the concept of selection of the patients who could profit from a given drug:                Mutation or amplification of EGFR receptor and erlotinib/gefitinib;        Mutations c-Kit/PDGFRa and imatinib;        Translocation of Bcr-Abl and imatinib;        Amplification of HER2 and HER2 inhibitors;        Amplification of TOP2A and anthracyclines;        Deletion of PTEN and mTOR inhibitors;        Amplification of FGFR1 and FGFR1 inhibitors;        ERCC1 negative-treatment and platinum salts;        RAS mutations and treatment of colon cancer        etc.        
In the case of breast cancer, prognostic molecular signatures, such as the tests Mamaprint® (developed by the Agendia company) or OncotypeDX® (company Genomic Health) are available. These signatures are used to determine if an auxiliary chemotherapy is necessary or not. But, although these tests make it possible to conclude on the need from an auxiliary chemotherapy, they do not make it possible to select the optimal therapy.
In short, the concept of personalized medicine corresponds to a selection of patients on biological criteria to increase the chances of response to a given therapy. Currently, these tests companion are rather used for the treatments by targeted therapies and make it possible to select the patients likely to profit from a given therapy but not to select the best therapy for a given patient. This is a major conceptual difference which constitutes the main interest of the present invention compared to the other markers proposed to date.
The anomalies of strong amplitude of the gene copy number (amplifications or deletions) modify the levels of gene expression. This mechanism of genomic deregulation is involved in the ontogenesis of many cancers. Amplifications of the EGFR gene are found in approximately 30% of lung cancers. The inhibition of EGFR in case of amplification is associated with a significant benefit in this same pathology. Similarly, MYCN is amplified in approximately 25% of the neuroblastoma and several studies showed the prognostic value of this anomaly in this pathology. Other oncogenes/anti-oncogenes (tumour suppressor genes) are frequently amplified/deleted in other types of tumours such HER, PTEN, PUTS, and the like.
Breast cancer presents an important frequency of chromosomal aberrations. Gene HER2 (ErbB2) is amplified in 10 to 20% of the cases. This amplification is associated with a hyper-expression of the Her2 protein and is involved in the tumoral transformation. A therapeutic strategy based on the targeting of this anomaly showed a benefit in the patients having HER2-positive breast cancer. In addition, the gene coding for the topoisomerase II is amplified in approximately 7% of breast cancers. This amplification is correlated with a good sensitivity to the anthracyclines, a class of drugs targeting the topoisomerase II. Other anomalies have often been observed in breast cancer. A1B1 gene is amplified in 10% of the cases, and leads to ontogenesis via the activation of AKT by the IGFR. FGF1R gene is amplified in 10% of case. The targeting of this protein by a tyrosine kinase inhibitor leads in vitro to a reduction of the cell multiplication. Similarly, amplifications of the genes EGFR, IGF1R or the deletions of PTEN can be treated by molecules targeting EGFR, IGF1R or mTOR, respectively.
In the scientific literature, certain works, among which those of A. Potti et al., propose a prediction of the drug's efficacy, primarily cytotoxicity, based on the analysis of the expression of genes selected from experiments on well-established cell lines (panel NCI60). These data allow the identification of expression profiles associated with the response for each tested molecule and this prediction is transposed to the human tumours. However, if this approach allows a molecule by molecule prediction, it does not allow the comparison of the efficacy of each molecule for a given patient in order to select the best drug. In addition, the one skilled in the art knows the limitations of in vitro model to perform in vivo predictions. These approaches tend to enrich the patient cohort for a given chemotherapy rather than to select a targeted individual therapy for a given patient on the basis of the intrinsic tumoral characteristics.
However, the choice of the appropriate chemotherapy in cancer treatment is a crucial issue. Indeed, most of the chemotherapies have very significant adverse effects and an erroneous choice (i.e., treatment without any therapeutic benefit) could lead to a cancer progression.
Up today, there is no marker efficient to select the most optimal therapeutic strategy for a given individual having a cancer. Accordingly, there is a strong need to methods of personalized medicine in the field of cancer treatment allowing the selection for a given individual of the most appropriate chemotherapy strategy.